Thieno(3,4-b)pyridine and thieno(3,4-c)pyridine

ABSTRACT

OF THE ABOVE-IDENTIFIED COMPOUNDS ONLY I,II,III, AND IV HAVE BEEN PREVIOUSLY PREPARED, SEE FOR EXAMPLE, L. H. KLEMM, C. E. KLOPFENSTEIN, R. ZELL, D. R. MCCOY AND R. A. KLEMM, J. ORG. CHEM., 34, 347 (1969) AND L. H. KLEMM, J. SHABTAI, D. R. MCCOY AND W. K. T. KIANG, J. HETEROCYCLIC CHEM., 5, 883 (1968).   SEE NAMED RINGS ABOVE   THIENO(3,4-B)PYRIDINE AND THIENO(3,4-C)PYRIDINE HAVE BEEN PREPARED. THERE ARE SIX THEORETICALLY POSSIBLE THIENOPYRIDINES, VIZ THIENO(2,3-B)PYRIDINE (I), THIENO(2,3-C)PYRIDINE (II), THIENO(3,2,-B)PYRIDINE (III), THIENO(3,2-C)PYRIDINE (IV), THIENO(3,4-B)PYRIDINE (V) AND THIENO(3,4-C)PYRIDINE (VI).

3,709,894 THIENO[3,4-b]PYRIDINE AND THIENO[3,4-c] PYRIDINE Le Roy H. Klemm, Eugene, Oreg., Wayne 0. Johnson,

Hatboro, Pa., and Danny V. White, Sacramento, Calif., assignors to Research Corporation, New York, N.Y. No Drawing. Filed Feb. 11, 1971, Ser. No. 114,671 Int. Cl. C07d 31/50 US. Cl. 260294.8 C 4 Claims ABSTRACT OF THE DISCLOSURE Thieno[3,4-b] pyridine and thieno[3,4-c]pyridine have been prepared.

There are six theoretically possible thienopyridines, viz thieno[2,3-b]pyridine (I), thieno[2,3-c]pyridine (II), thieno[3,2-b]pyridine (III), thieno[3,2-c]pyridine (IV), thieno[3,4-b]pyridine (V) and thieno[3,4-c]pyridine (VI).

Of the above-identified compounds only I, II, III and IV have been previously prepared, see for example, L. H. Klemm, C. E. Klopfenstein, R. Zell, D. R. McCoy and R. A. Klemm, J. Org. Chem., 34, 347 (1969) and L. H. Klemm, J. Shabtai, D. R. McCoy and W. K. T. Kiang, J. Heterocyclic Chem, 5, 883 (1968).

There is pharmacological interest in the thienopyridines in that they are isosteric with quinoline and isoquinoline systems. Additionally, the thienopyridines are useful for the preparation of dyes and dyestuifs, biocides, e.g. antimalarials, herbicides, pesticides and as an additive to lubricating oils. For example, the above-identified thienopyridine's may be incorporated in petroleum lubrieating oils in amounts in the range 0.011.0% by Weight to improve the lubricating and extreme pressure properties of the lubricating oils.

It is an object of this invention to provide thienopyridines and derivatives thereof not heretofore available.

It is another object of this invention to provide a process for the manufacture of certain thienopyridines, particularly thieno[3,4-b]pyridine and thieno[3,4-c]pyridine and derivatives thereof, such as halogen, e.g. Cl, F and Br, -NO phenyl, acetoxy, hydrogen, carboalkoxy and cyano-substituted derivatives thereof.

How these and other objects of this invention are achieved will become apparent in the light of the accompanying disclosure. In at least one embodiment of the practice of this invention at least one of the foregoing objects will be achieved.

Thienopyridines, not available heretofore, have been prepared. Specifically, thieno[3,4-b]pyridine has been prepared and thieno[3,4-c]pyridine has been prepared.

In accordance with this invention 2,3-dimethylpyridine and 3,4-dimethylpyridine have been converted into thieno [3,4-b1pyridine (V) and thieno[3,4-c]pyridine (VI), respectively. By employing the practices of this invention United States Patent ice derivatives of (V) and (VI) with selected substituents, such as a chloro group, in the pyridine ring are prepared by starting with a suitably substituted dimethylpyridine.

The preparation of thieno[3,4-b]pyridine (V) from 2,3-dimethylpyridine in accordance with one embodiment of this invention is schematically illustrated hereinafter in Scheme A.

Scheme A N-C1, A

OH! 11201 Nags Ha 4 on Cl 2 N 2. H01 f VII VIII The preparation of thieno [3,4-c1pyridine from 3,4-dimethylpyridine in accordance with another embodiment of this invention is schematically illustrated hereinafter in Scheme B.

The preparation of thieno[3,4-b]pyridine in accordance with one embodiment of the practice of this invention as schematically illustrated in accordance with Scheme A hereinabove is as follows: A vigorously stirred solution of 10 ml. (9.4 g., 0.088 mol) of 2,3-dimethylpyridine and 24 g. (0.18 mol) of N-chlorosuccinimide in 900 ml. of CCL, was refluxed under nitrogen gas in a round-bottom flask while it was irradiated by means of a juxtaposed 200- watt Hanovia lamp for 24 hours. The mixture was cooled, filtered to remove succinimide and unreacted N-chlorosuccinimide, treated with fresh N-chlorosuccinimide (24 g.), and reacted further for an additional 24 hours.

The cooled reaction mixture was filtered and treated with excess anhydrous HCl. The gummy precipitate was crystallized from isopropanol to give 14.3 g. (77%) of VII: M.P. 148.5-1495".

A sample for analysis was recrystallized from isopropanol and sublimed three times (once just prior to analysis) at 80 (0.1 mm.) to give a white solid: M.P. l47.5-l48.5 (dec.)

Analysis.-Calcd. for CqHgCigN (percent): C, 39.56; H, 3.79; Cl, 50.05; N, 6.59. Found (percent): C, 39.70; H, 4.10; Cl, 49.94; N, 6.65.

To a stirred solution of 60 g. (excess) of Na S.9H O in 600 ml. of 80% aqueous EtOH was added, dropwise over a period of 6 hours and in an atmosphere of nitrogen, a solution of 10.1 g. of hydrochloride VII in 150 ml. of absolute EtOH. The residue from evaporation of the solvent was treated With water and extracted with benzene. Evaporation of the dried (Na SO extract and chromatography by means of Florisil, benzene, and CHC1 gave 3.8 g. (59% from 2,3-dimethylpyridine) of VIII. Since VIII was unstable in air it was used immediately in the next step.

To a cold (-5), stirred solution of 3.05 g. (0.022 mole) of sulfide VIII in 30 ml. of CH CN, 7 ml. of water, and 8 ml. of Et N was added, dropwise over a period of 2 hours, a solution of 12 g. (0.044 mol) of iodobenzene dichloride in 275 ml. of CH CN. The mixture was stirred overnight at room temperature and evaporated to dryness. The residue was treated with benzene, filtered to remove Et NHCl, and chromatographed by means of Florisil (100 g.) and EtOAc containing 0-15% MeOH. Sulfoxide IX, 1.9 g. (56%), was obtained from the eluent as a colorless liquid; infrared band (in CHCI at 1050-1030 cm." (:0).

To a cold (0), stirred solution of 2.3 g. (0.017 mol of sulfide VIII in 100 ml. of methylene dichloride was added, dropwise over a period of 12 hours, a solution of 3.44 g. (85% purity, 0.017 mol) of m-chloroperbenzoic acid in 100 ml. of the same solvent. The mixture was stirred at 0 for 24 hours and at -20 for 48 hours. It was filtered to remove some of the m-chlorobenzoic acid which formed. The filtrate was washed with aqueous NaHCO dried (Na SO and evaporated. The residue was chromatographed by means of Florisil with solvents which were varied from CHCl (used first) through EtOAc to MeOH. Eluted in CHCl and CHCl -EtOAc (2:3) was the sulfone 1,3-dihydroth1eno[3,4-b]pyridine 2,2-dioxide X, 0.73 g. (25%). Eluted as previously indicated was sulfoxide IX, 0.87 g. (34%).

Sulfone X crystallized from EtOAc as slightly yellow prisms: M.P. 128-129"; infrared bands (in CHCl at 1330 and 1130 cm. (sulfone).

Analysis.-Calcd. for CqHqNOgS (percent): C, 49.69; H, 4.17; N, 8.28; S, 18.95. Found (percent): C, 49.95; H, 4.09; N, 8.03; S, 19.18.

A solution of 0.46 g. of freshly prepared sulfoxide IX in 5 ml. of CHCL, was mixed with 1.54 g. of Woelm neutral alumina (activity I). The solvent was evaporated in vacuo and the residue was heated in a molecular still at 100-120 mm.) for 1 hour. The distillate (V), 0.365 g. (90%), was a yellow liquid which darkened on standing in the laboratory; UV. max. (95% EtOH) 224 nm (e 18600), 293 (6400), 297 sh'oulder (603 0), 306 (7590), 343 (2850); UV. max. (95% EtOH-l-HCI) 232 nm (6 14300), 303 shoulder (11700), 308 (13700), 388 (2580), ii (neat) 1500 (C=C and C=N), 865 lone aromatic hydrogen), 800 and 775 cm.- (3 vicinal aromatic hydrogenls); mass spectral parent peak (most abundant) at rn/e 135; nmr (CDCI 60 mHz) 6 6.90 (d of d, l, 1 :3] Hz, I =8.5 Hz, H-6), 7.66 (d, 1, I =3.2 Hz., H-1), 7.78-8.02 (m, 2, H-3 and H-7), 8.57 (d of d, l, J5,7=1.8 Hz., H-5); nmr (CF CO H, 100 mHz.) 6 7.67 (d of d, l, J =5.5 Hz., J -;=8.5 Hz., H-6), of d, l, J1I3=3.2 Hz., J3 q'=0.7 Hz., H-3), d, 1, H-l), 8.4-9.1 (m, 2, H-5 and H-7).

A picrate formed yellow prisms from EtOH: M.P. (sealed tube) 207.5-209 (darkening).

AnaIysis.Calcd. for C H N SO (percent): C, 42.86; H, 2.21; N, 15.38; S, 8.80. Found (percent): C, 43.18; H, 2.27; N, 15.05; S, 8.55.

The preparation of thieno[3,4-c] pyridine in accordance with one embodiment of the practice of this invention as schematically illustrated in accordance with Scheme B hereinabove is as follows: In the same manner as used to photochlorinate 2,3-dirnethylpyridine, as described hereinbefore, a stirred, refluxing solution of 3,4-dimethylpyridine (4 g., 0.037 mol) and N-chlorosuccinimde (14 g., 0.1 mole) in 1.5 l. of CCL; was irradiated for 7.5 hours in a nitrogen atmosphere. Filtration of the cooled reaction mixture and treatment of the filtrate with anhydrous HCl gave XI as a gum which crystallized on standing at 3. It was recrystallized from acetone and sublimed slowly at IOU-120 (0.3 mm.) to give 5.2 g. (67%) of white solid, M.P. 157-159 (dec.).

AnaIysis.--Ca1cd. for C I-I Cl N (percent): C, 39.56; H, 3.79; Cl, 50.05; N, 6.59. Found (percent): C, 39.55; H, 3.77; Cl, 50.27; N, 6.57.

1,3 dihydrothieno[3,4-c]pyridine, XII, was prepared from XI in a manner closely similar, as described hereinbefore, to that used for its isomer VIII. However, to avoid decomposition of the product, the reaction mixture was treated directly (without preceding evaporation) with an equal volume of benzene. This mixture was then washed with water, dried, and evaporated to give XII as a slightly yellow liquid (83%) which was not purified father. The picrate, formed in absolute EtOH was obtained as canary yellow crystals from hexane-CH Cl M.P. 180 (dec.).

Analysis.Calcd. for C I-1 1 1 (percent): C, 42.63; H, 2.75; N, 15.30. Found (percent): C, 42.53; H, 2.69; N, 15.29.

1,3-dihydrothieno[3,4-c]pyridine 2-oxide, XIII, was prepared by oxidation of XII with iodobenzene dichloride in the manner used to convert VIII to IX. Chromatography by means of Florisil plus benzene (to remove iodobenzene formed) and then 0-15% MeOH in EtOAc gave XIII (67%) as a red-brown liquid; infrared band (in CI-ICl at 1055-1040 cm." (5:0).

In the manner used for the preparation of V, a deposit of fresh sulfoxide XIII on alumina was heated at (but at 0.3 mm.) to give VI as a slightly yellow liquid (37%); LR. (neat) 1600 (C=C and C'=N), 865 cm? (lone aromatic hydrogen); UV. max. (abs. EtOI-I) 224 nm. (6 20900), 270 shoulder (2240), 280 (2890), 291 (2050), 342 (2960); UV. max (96% EtOH-i-HCI) 236 nm. (c 24200), 281 (4900), 290 (3470), 380 (2740); nmr (CDCl 60 mHz.) 6 7.38 (slightly split d, 1, J -1=6.5 Hz., H-7), 7.64 (d, l, 1 :3 Hz., H-3 or H-1), 8.02 (d, 1, H-l or H-3), 8.04 (d overlapping 8.02 signal, 1, H-6), 9.12 (broadened s, 1, H-4).

The picrate, formed in absolute EtOH, was obtained as yellow needles from benzene-hexane: M.P. 234-235 (dec.).

Analysis.-Calcd. for C H N SO (percent): C, 42.86; H, 2.21; N, 15.38; S, 8.80. Found (percent): C, 42.76; H, 2.10; N, 15.22 S, 8.63.

As will be apparent to those skilled in the art in the light of the foregoing disclosure many modifications, alterations and substitutions are possible in the practice of this invention without departing from the spirit or scope thereof.

We claim:

1. A method for the preparation of thieno[3,4-b]pyridine which comprises reacting 2,3-dimethylpyridine and N- chlorosuccinimide in an inert solvent while refluxing the resulting reaction mixture under an inert gas and irradiating the refluxing reaction mixture with ultraviolet radiation, cooling and filtering the resulting reaction mixture to remove succinimide and unreacted N-chlorosuccinimide, reacting the resulting cooled and filtered reaction mixture with excess anhydrous HCl and recovering therefrom the resulting bis-chloromethyl derivative as the hydrochloride salt having the formula,

' CHeCl CH2Cl reacting the resulting recovered bis-chloromethyl hydrochloride derivative with ethanolic sodium sulfide to produce the corresponding sulfide derivative having the formula,

oxidizing the resulting sulfide derivative by reaction with iodobenzene dichloride in the presence of aqueous acetonitrile and triethylamine to produce the resulting sulfoxide having the formula,

recovering the resulting sulfoxide and heating a solution of said sulfoxide in the presence of activated alumina under reduced pressure and at an elevated'temperature to produce a distillate fraction the aforesaid thieno[3,4-b] pyridine having the formula,

bis-chloromethyl derivative as the hydrochloride salt having the formula,

l CHzCl h (:1 reacting the recovered bis-chloromethyl hydrochloride derivative with ethanolic sodium sulfide to produce the corresponding sulfide derivative having the formula,

oxidizing the resulting sulfide derivative by reaction with iodobenzenedichloride in the presence of aqueous acetonitrile and triethylamine to produce the resulting sulfoxide having the formula,

recovering the resulting sulfoxide and heating a solution of said sulfoxide in the presence of activated alumina under reduced pressure and at an elevated temperature to produce the aforesaid thieno[3,4-c]pyridine having the formula,

3. The compound thieno[3,4-b]pyridine. 4. The compound thieno[3,4-c]pyridine.

References Cited UNITED STATES PATENTS 3,632,592 1/1972 Nakanishi et al. 260-294.8 C

ALAN L. ROTMAN, Primary Examiner US. Cl. X.R.

260-290 HL; 204-158 R; 252-47 

